Sibutramine (N-[1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine), which is a inhibitor of 5-hydroxytryptamine and noradrenaline reuptake in vivo (Neuropharmacology, 28, p129-134), is useful in the treatment of depression, Parkinson's disease, obesity, insulin-independent diabetes mellitus, epilepsy, and the like. In addition, sibutramine reduces body weight gain by a dual action to reduce food intake by enhancing satiety and to increase energy expenditure by stimulating heat generation (Int. J. Obesity, 19, p145; Brit. J. Pharmacol. 114, p388).
Since sibutramine is difficult to purify due to its low melting point, it is preferable to use a crystalline material capable of being purified by recrystallization in order to prepare a pharmaceutical composition comprising sibutramine. Korean Pat. Publication No. 1990-0000274 discloses that sibutramine is utilized as salts formed with acids providing non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, in the form of hydrochloride, malate, acetate, citrate, fumarate, tartrate, succinate, aspartate or glutmate salt. However, since sibutramine hydrochloride is difficult to handle pharmaceutically due to its hygroscopic nature, it is undesirable to use sibutramine hydrochloride for preparing medicaments. In the preparation of medicaments, a constant weight of an active compound should be contained in each dosage form, but an active ingredient absorbing water from the surrounding environment makes it difficult to achieve such consistency. Korean Pat. Publication No. 94-8913 discloses that when sibutramine hydrochloride is prepared in a monohydrate form, a non-hygroscopic product is obtained, which is suitable for the preparation of capsules, tablets and other pharmaceutical dosage forms.
The therapeutic use of sibutramine in depression is described in British Pat. No. 2098602. The therapeutic use of sibutramine in Parkinson's disease is disclosed in International Pat. Publication No. WO88/06444. The therapeutic use of sibutramine in cerebral function disorders is disclosed in U.S. Pat. No. 4,939,175. The use of sibutramine hydrochloride in the treatment of obesity is disclosed in European Pat. No. 397831. Also, International Pat. Publication No. WO95/20949 discloses the use of sibutramine for improving impaired glucose tolerance or glucose tolerance in patients suffering from insulin-independent diabetes mellitus.
In addition, Brazilian Pat. Publication No. 0105486 discloses a novel salt of sibutramine, sibutramine sulfate, in which two moles of sibutramine are bonded to one mole of sulfuric acid. However, this compound is structurally different from sibutramine hydrogen sulfate (in which one mole of sibutramine is bonded to one mole of sulfuric acid) according to the present invention. In particular, the Brazilian Patent Publication never mentions crystalline forms or physical properties, such as solubility and stability, of the novel salt.
Typically, the preparation of salts having pharmaceutically useful physical properties must satisfy the following physicochemical criteria: (1) good solubility, (2) good stability, (3) good non-hygroscopicity and (4) compressibility into tablet form.
However, Korean Pat. Publication No. 94-8913 states that sibutramine hydrochloride has been known to contain a variable amount of water and thus be hygroscopic, and that non-hygroscopic sibutramine can be obtained by preparing sibutramine hydrochloride in a monohydrate form. Sibutramine hydrochloride monohydrate has been prepared by brining it into contact with a medium consisting of water or a medium containing water.
Thus, sibutramine hydrochloride monohydrate is prepared by a complicated process including adding a predetermined amount of water to a reaction mixture, or including preparing sibutramine hydrochloride anhydrate and suspending the sibutramine hydrochloride anhydrate in a water-containing solvent for a long time with agitation. In addition, since currently available sibutramine hydrochloride monohydrate has relatively low solubility between pH 1.0 and pH 7.4, substitute salts having better solubility need to be developed in order to improve the bioavailability of sibutramine. The term “sibutramine”, as used herein, refers to racemic sibutramine, unless otherwise indicated.
Based on this background, the present inventors found that hydrogen sulfate and bromate salts of sibutramine possess remarkably high solubility in water as well as having non-hygroscopicity and stability, and that sibutramine phosphate hydrate has greatly enhanced solubility even when it exists in a hydrous form, compared to conventional sibutramine hydrochloride hydrate, thereby leading to the present invention.